Failure of thymic deletion and instability of autoreactive Tregs drive autoimmunity in immune-privileged liver

Abstract

The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II–restricted model peptide in hepatocytes by autoreactive CD4 + T cells. We found that the hepatic peptide was not expressed in the thymus, leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4 + T cells. In the liver, autoreactive CD4 + effector T cells accumulated within portal ectopic lymphoid structures and maturated toward pathogenic IFN-γ and TNF coproducing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs but not of nonspecific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation, and reduced expression of Foxp3 . As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared with that of nonspecific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.

Harnessing the liver to induce antigen-specific immune tolerance

“…Although MHC I expression is low, hepatocytes can prime CD8 T cells, which mostly results in CD8 T cell death [ 35 , 36 ] or profound unresponsiveness even in infection [ 37 ]. MHC II expression is low or absent in steady-state [ 38 ], but can be upregulated in inflammatory conditions, rendering hepatocytes functional antigen-presenting cells that promote tolerance rather than inflammation [ 39 , 40 ]. Besides direct antigen presentation by hepatocytes, it is conceivable that hepatocytes can also deliver antigen to neighbouring professional antigen-presenting cells, e.g.…”

Animal Models for Autoimmune Hepatitis: Are Current Models Good Enough?

“…Recently, Preti et al. investigated the role of autoreactive CD4 T cells in an LCMV-related AIH model ( 27 ). They constructed a transgenic mouse in which the CLIP sequence of the CD74 has been replaced by the immunodominant CD4 epitope GP 61-80 specifically in the liver.…”

“…Interestingly, they found that besides an activation of liver-infiltrating CD4 T cells, the mice also displayed a reduced functionality of GP-specific regulatory T cells. In combination a chronic form of AIH-like disease, with interface hepatitis, formation of autoantibodies, as well as elevated IgG and ALT levels ensued ( 27 ). Although, this model uses modified autoantigen-presentation and autoantigen-specific TcR, these data indicate that the tolerogenic environment in the liver might be overcome via autoreactive CD4, rather than CD8, T cells.…”

Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies

“…In a mouse model of AIH, characterized by hepatocellular expression of a MHC-class II restricted immunodominant epitope of the lymphocyte choriomeningitis virus and by accumulation of CD4 T-cells specifically recognizing this epitope, Preti et al. proposed that liver damage was fostered by selective failure of peripherally induced autoreactive Tregs ( 81 ). Notably these autoreactive Tregs not only were reduced in frequency but also displayed heightened IL-17 production and reduced epigenetic demethylation ( 81 ), postulating a role for altered epigenetic regulation in Treg impairment in this model.…”

“…In a mouse model of AIH, characterized by hepatocellular expression of a MHC-class II restricted immunodominant epitope of the lymphocyte choriomeningitis virus and by accumulation of CD4 T-cells specifically recognizing this epitope, Preti et al proposed that liver damage was fostered by selective failure of peripherally induced autoreactive Tregs (81). Notably these autoreactive Tregs not only were reduced in frequency but also displayed heightened IL-17 production and reduced epigenetic demethylation (81), postulating a role for altered epigenetic regulation in Treg impairment in this model. In human AIH, FOXP3 demethylation -a typical feature of bona fide Tregs -was retained in some studies (75,79) and altered in others, where AIH derived Tregs were highly methylated (82); this indicates that further studies are needed to clearly establish the role of FOXP3 epigenetic regulation in AIH Tregs.…”